Body fatness contributes to a substantial proportion of the premature deaths in the U.S., including 15-20% of cancer mortality. The impact is greater among ethnic minorities because they tend to accumulate more visceral fat that bears a higher metabolic risk. The unabated obesity epidemic and lack of sustainable weight control interventions may improve if we understand obesity better as a brain disease and a dysregulation of the brain-gut-adiposity axis. The brain is long known to regulate energy homeostasis based on fuel availability signals originating from the gut and adipose tissue but appears to be altered structurally and metabolically in obesity, which may perpetuate the positive energy balance. Obesity has been associated with a smaller brain volume, deleterious neurochemical imbalance, and cognitive impairment. Obesity-prone eating behaviors and anabolic dietary composition have been similarly associated with brain alterations. Also, the colonic microbiota has recently been shown to be associated with brain chemistry, anxiety behaviors and adiposity. Leveraging recent advances in brain and body composition imaging and in molecular technology, we propose to investigate the brain-gut-adiposity axis for novel inter-relationships across brain imaging characteristics, gut microbial profiles and visceral fat content. We will add a brain MRI study to an ongoing Program Project grant, where we are assessing visceral and hepatic fat with whole-body DXA and abdominal MRI in 2,000 women and men of five ethnic groups from the Multiethnic Cohort Study to examine the relationship of visceral/liver fat to gut microbiota phylogeny based on 16S rRNA gene sequencing and to habitual dietary intakes using eating behavior and food frequency questionnaires. We will conduct brain MR imaging (MRI) and proton MR spectroscopy (1H MRS) to assess brain imaging characteristics (macro- and micro-structural morphology, neurometabolite levels) in a subgroup of 100 program project participants from three ethnic groups (Japanese American, Native Hawaiian, white) in Hawaii. Our specific aims are to determine the association of these structural and neurochemical brain traits with (1) visceral and hepatic fat content, (2) eating behaviors and dietary composition, and (3) gut microbial community profiles. We hypothesize that lower total and regional brain volumes, higher levels of glial metabolite myoinositol, indicative of inflammation, and lower neuronal metabolite N-acetylaspartate will be associated with greater amounts of visceral and liver fat, a higher tendency for obesity-prone eating behaviors (external, emotional, routinely restrained eating) and anabolic dietary composition (high in refined carbohydrates, saturated fat), and altered and less diverse gut microbial profiles Cognitive functions will be assessed with the NIH Toolbox and correlated to brain MRI, dietary intake, and gut bacteria measurements. This innovative line of research has a great potential to lead to more effective and better targeted obesity intervention strategies.